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1.
Int J Biol Macromol ; 281(Pt 4): 136504, 2024 Oct 10.
Artículo en Inglés | MEDLINE | ID: mdl-39395513

RESUMEN

Osteoporosis is a systemic disease with complex etiology and high prevalence, resulting in a huge economic burden. For a long time, the search for new therapeutic pharmaceuticals has never stopped. Bone loss is related to the imbalance between bone resorption by osteoclasts and bone formation by osteoblasts. In recent years, the role of immunity and inflammation in the development of osteoporosis has studied well. For example, various cytokines, chemokines and endocrine factors regulate osteoclastogenesis via activating different macrophage subtypes, including pro-inflammatory M1 and anti-inflammatory M2. Bilobalide (Bil), an active Ginkgo biloba ingredient, has garnered great interest because of its anti-oxidant and anti-inflammatory activities. In this study, we found that Bil can attenuate osteoclast generation induced by receptor activator of nuclear factor- kappa B ligand (RANKL) through upregulating the sirtuin 3 (SIRT3) and negatively regulating NF-κB signaling. Furthermore, Bil promotes M2 polarization of macrophages in a dose-dependent manner. In vivo studies provided evidence that Bil improves bone density in osteoporosis mice models. Based on the above results, we have reason to believe that Bil has potential therapeutic value in osteoclast-mediated bone loss and offers an effective option for long-term osteoporosis management.

2.
BMC Pediatr ; 24(1): 627, 2024 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-39354420

RESUMEN

BACKGROUND: Prader-Willi syndrome (PWS) is a rare multisystemic hereditary illness. Recombinant human growth hormone (rhGH) therapy is widely recognized as the primary treatment for PWS. This study aimed to examine how different PWS genotypes influence the outcome of rhGH treatment in children with PWS. METHODS: A review was conducted on 146 Chinese children with PWS, genetically classified and monitored from 2017 to 2022. Unaltered and modified generalized estimating equations (GEE) were employed to examine the long-term patterns in primary outcomes (growth metrics) and secondary outcomes (glucose metabolism metrics and insulin-like growth factor-1 (IGF-1)) during rhGH therapy. The study also evaluated the prevalence of hypothyroidism, hip dysplasia, and scoliosis before and after rhGH treatment. RESULTS: Children with PWS experienced an increase in height/length standard deviation scores (SDS) following rhGH administration. The impact of rhGH therapy on growth measurements was similar in both the deletion and maternal uniparental diploidy (mUPD) cohorts. Nevertheless, the deletion group was more prone to insulin resistance (IR) compared to the mUPD group. No significant variations in growth metrics were noted between the two groups (P > 0.05). At year 2.25, the mUPD group showed a reduction in fasting insulin (FINS) levels of 2.14 uIU/ml (95% CI, -4.26, -0.02; P = 0.048) and a decrease in homeostasis model assessment of insulin resistance (HOMA-IR) of 0.85 (95% CI, -1.52, -0.17; P = 0.014) compared to the deletion group. Furthermore, there was a decrease in the IGF standard deviation scores (SDS) by 2.84 (95% CI, -4.84, -0.84; P = 0.005) in the mUPD group during the second year. The frequency of hip dysplasia was higher in the mUPD group compared to the deletion group (P < 0.05). CONCLUSIONS: rhGH treatment effectively increased height/length SDS in children with PWS, with similar effects observed in both deletion and mUPD genotypes. Children with mUPD genetype receiving rhGH treatment may experience enhanced therapeutic effects in managing PWS.


Asunto(s)
Genotipo , Hormona de Crecimiento Humana , Síndrome de Prader-Willi , Humanos , Síndrome de Prader-Willi/tratamiento farmacológico , Síndrome de Prader-Willi/genética , Hormona de Crecimiento Humana/uso terapéutico , Niño , Femenino , Masculino , Preescolar , Factor I del Crecimiento Similar a la Insulina , Adolescente , Resultado del Tratamiento , Proteínas Recombinantes/uso terapéutico , Lactante , Hipotiroidismo/tratamiento farmacológico , Hipotiroidismo/genética , Resistencia a la Insulina
3.
Ital J Pediatr ; 50(1): 207, 2024 Oct 08.
Artículo en Inglés | MEDLINE | ID: mdl-39380047

RESUMEN

Mucopolysaccharidosis type II (MPS II) is a rare X-linked recessive inherited lysosomal storage disease. With pathogenic variants of the IDS gene, the activity of iduronate-2-sulfatase (IDS) is reduced or lost, causing the inability to degrade glycosaminoglycans (GAGs) in cells and influencing cell function, eventually resulting in multisystemic manifestations, such as a coarse face, dysostosis multiplex, recurrent respiratory tract infections, and hernias. Diagnosing MPS II requires a combination of clinical manifestations, imaging examinations, urinary GAGs screening, enzyme activity, and genetic testing. Currently, symptomatic treatment is the main therapeutic approach. Owing to economic and drug availability issues, only a minority of patients opt for enzyme replacement therapy or hematopoietic stem cell transplantation. The limited awareness of the disease, the lack of widespread detection technology, and uneven economic development contribute to the high rates of misdiagnosis and missed diagnosis in China.


Asunto(s)
Mucopolisacaridosis II , Humanos , Mucopolisacaridosis II/diagnóstico , Mucopolisacaridosis II/terapia , Terapia de Reemplazo Enzimático , Trasplante de Células Madre Hematopoyéticas , Pruebas Genéticas , Iduronato Sulfatasa/uso terapéutico
4.
Mol Cytogenet ; 17(1): 18, 2024 Jul 29.
Artículo en Inglés | MEDLINE | ID: mdl-39075593

RESUMEN

BACKGROUND: Maternal uniparental disomy for chromosome 6 (upd(Cajaiba MM, Witchel S, Madan-Khetarpal S, Hoover J, Hoffner L, Macpherson T, et al. Prenatal diagnosis of trisomy 6 rescue resulting in paternal UPD6 with novel placental findings. Am J Med Genet Part A. 2011;155 A(8):1996-2002.)mat) has been previously reported to cause intrauterine growth restriction (IUGR), but the specific clinical phenotype has not been defined. Based on clinical data from two new cases and patients from the literature, specific phenotypes and mechanisms will be discussed further. CASE PRESENTATION: In case 1, a maternal isodisomy mixed with a heterodisomy was found on chromosome 6, including a regional absence of heterozygosity between 6q23.3 and 6q27. In case 2, a homozygous SCUBE3 mutation and upd(Cajaiba MM, Witchel S, Madan-Khetarpal S, Hoover J, Hoffner L, Macpherson T, et al. Prenatal diagnosis of trisomy 6 rescue resulting in paternal UPD6 with novel placental findings. Am J Med Genet Part A. 2011;155 A(8):1996-2002.)mat, involving the 6p21.1-25.1 region were found. Clinical data related to upd(Cajaiba MM, Witchel S, Madan-Khetarpal S, Hoover J, Hoffner L, Macpherson T, et al. Prenatal diagnosis of trisomy 6 rescue resulting in paternal UPD6 with novel placental findings. Am J Med Genet Part A. 2011;155 A(8):1996-2002.)mat were also reviewed. Of all the 21 reported cases with upd(Cajaiba MM, Witchel S, Madan-Khetarpal S, Hoover J, Hoffner L, Macpherson T, et al. Prenatal diagnosis of trisomy 6 rescue resulting in paternal UPD6 with novel placental findings. Am J Med Genet Part A. 2011;155 A(8):1996-2002.)mat (including our 2 cases), 18 (85.7%) presented IUGR. CONCLUSIONS: The phenotypes of the two newly identified patients with upd(Cajaiba MM, Witchel S, Madan-Khetarpal S, Hoover J, Hoffner L, Macpherson T, et al. Prenatal diagnosis of trisomy 6 rescue resulting in paternal UPD6 with novel placental findings. Am J Med Genet Part A. 2011;155 A(8):1996-2002.)mat further suggest that IUGR is associated with upd(Cajaiba MM, Witchel S, Madan-Khetarpal S, Hoover J, Hoffner L, Macpherson T, et al. Prenatal diagnosis of trisomy 6 rescue resulting in paternal UPD6 with novel placental findings. Am J Med Genet Part A. 2011;155 A(8):1996-2002.)mat and case 2 is the first reported upd(Cajaiba MM, Witchel S, Madan-Khetarpal S, Hoover J, Hoffner L, Macpherson T, et al. Prenatal diagnosis of trisomy 6 rescue resulting in paternal UPD6 with novel placental findings. Am J Med Genet Part A. 2011;155 A(8):1996-2002.)mat patient with a homozygous SCUBE3 gene mutation. However, the specific phenotypes involved in upd(Cajaiba MM, Witchel S, Madan-Khetarpal S, Hoover J, Hoffner L, Macpherson T, et al. Prenatal diagnosis of trisomy 6 rescue resulting in paternal UPD6 with novel placental findings. Am J Med Genet Part A. 2011;155 A(8):1996-2002.)mat and the related mechanisms need to be further studied.

5.
Reprod Sci ; 2024 Jun 21.
Artículo en Inglés | MEDLINE | ID: mdl-38907129

RESUMEN

To investigate the impact of Sitagliptin against obesity and the underlying mechanism. Obese immature mice were treated with 10, 30, and 90 mg/kg Sitagliptin, respectively. The body weights were recorded and the level of serum biochemical indexes were detected. The visceral fat ratio of each mouse was determined. The pathological change in adipose tissues was determined by HE staining, while F4/80 and CD206 levels in adipose tissues were determined by the immunohistochemical analysis. Lipid formation was evaluated by Oil red O staining assay. RAW264.7 cells were stimulated using oxLDL, followed by being incubated with different concentrations of Sitagliptin. The release of ADPN, IL-6, IL-1ß, TNF-α, and the activity of SOD, was measured by ELISA assay. Western blotting was applied to determine adipsin, Nrf2, Keap1, and HO-1 protein levels. ROS level was checked using the DCFH-DA assay. RT-PCR assay was utilized to detect the mRNA levels of IL-6, IL-1ß, TNF-α, Nrf2, Keap1, and HO-1. The body weight gain, infiltration of multinucleated cells, enlarged size of adipocytes, increased lipid accumulation, elevated visceral fat ratio, declined ADPN level, upregulated adipsin, and disordered serum biochemical indexes in obese immature mice were statistically significantly reversed by Sitagliptin. Excessive release of inflammatory factors and upregulated F4/80 and CD206 were observed in obese immature mice, which were statistically significantly repressed by Sitagliptin. Furthermore, the elevated MDA level, increased SOD activity, and inhibited Nrf2 pathway in obese immature mice were significantly reversed by Sitagliptin. In oxLDL stimulated RAW264.7 cells, increased release of inflammatory factors, ROS, and MDA, elevated SOD activity, and inactivated Nrf2 pathway were observed, which were statistically significantly abolished by the treatment of Sitagliptin. Sitagliptin alleviated obesity in immature mice by inhibiting inflammation and oxidative stress.

6.
Mol Genet Genomic Med ; 12(4): e2439, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38613222

RESUMEN

OBJECTIVE: To characterize the phenotype spectrum, diagnosis, and response to growth-promoting therapy in patients with ACAN variants causing familial short stature. METHODS: Three families with ACAN variants causing short stature were reported. Similar cases in the literature were summarized, and the genotype and phenotype were analyzed. RESULTS: Three novel heterozygous variants, c.757+1G>A, (splicing), c.6229delG, p.(Asp2078Tfs*1), and c.6679C>T, p.(Gln2227*) in the ACAN gene were identified. A total of 314 individuals with heterozygous variants from 105 families and 8 individuals with homozygous variants from 4 families were confirmed to have ACAN variants from literature and our 3 cases. Including our 3 cases, the variants reported comprised 33 frameshift, 39 missense, 23 nonsense, 5 splicing, 4 deletion, and 1 translocation variants. Variation points are scattered throughout the gene, while exons 12, 15, and 10 were most common (25/105, 11/105, and 10/105, respectively). Some identical variants existing in different families could be hot variants, c.532A>T, p.(Asn178Tyr), c.1411C>T, p.(Gln471*), c.1608C>A, p.(Tyr536*), c.2026+1G>A, (splicing), and c.7276G>T, p.(Glu2426*). Short stature, early-onset osteoarthritis, brachydactyly, midfacial hypoplasia, and early growth cessation were the common phenotypic features. The 48 children who received rhGH (and GnRHa) treatment had a significant height improvement compared with before (-2.18 ± 1.06 SD vs. -2.69 ± 0.95 SD, p < 0.001). The heights of children who received rhGH (and GnRHa) treatment were significantly improved compared with those of untreated adults (-2.20 ± 1.10 SD vs. -3.24 ± 1.14 SD, p < 0.001). CONCLUSION: Our study achieves a new understanding of the phenotypic spectrum, diagnosis, and management of individuals with ACAN variants. No clear genotype-phenotype relationship of patients with ACAN variants was found. Gene sequencing is necessary to diagnose ACAN variants that cause short stature. In general, appropriate rhGH and/or GnRHa therapy can improve the adult height of affected pediatric patients caused by ACAN variants.


Asunto(s)
Enanismo , Hormona de Crecimiento Humana , Adulto , Niño , Humanos , Agrecanos , Genotipo , Heterocigoto , Homocigoto , Pacientes , Fenotipo
7.
Orphanet J Rare Dis ; 19(1): 179, 2024 Apr 29.
Artículo en Inglés | MEDLINE | ID: mdl-38685110

RESUMEN

Mucopolysaccharidoses (MPSs) are caused by a deficiency in the enzymes needed to degrade glycosaminoglycans (GAGs) in the lysosome. The storage of GAGs leads to the involvement of several systems and even to the death of the patient. In recent years, an increasing number of therapies have increased the treatment options available to patients. Early treatment is beneficial in improving the prognosis, but children with MPSs are often delayed in their diagnosis. Therefore, there is an urgent need to develop a method for early screening and diagnosis of the disease. Tandem mass spectrometry (MS/MS) is an analytical method that can detect multiple substrates or enzymes simultaneously. GAGs are reliable markers of MPSs. MS/MS can be used to screen children at an early stage of the disease, to improve prognosis by treating them before symptoms appear, to evaluate the effectiveness of treatment, and for metabolomic analysis or to find suitable biomarkers. In the future, MS/MS could be used to further identify suitable biomarkers for MPSs for early diagnosis and to detect efficacy.


Asunto(s)
Mucopolisacaridosis , Espectrometría de Masas en Tándem , Humanos , Mucopolisacaridosis/diagnóstico , Mucopolisacaridosis/metabolismo , Espectrometría de Masas en Tándem/métodos , Biomarcadores/metabolismo , Glicosaminoglicanos/metabolismo
8.
Mol Genet Genomic Med ; 12(4): e2433, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38591167

RESUMEN

BACKGROUND: Kenny-Caffey syndrome type 2 (KCS2) is an extremely rare inherited disorder characterized by proportionate short stature, skeletal defects, ocular and dental abnormalities, and transient hypocalcemia. It is caused by variants in FAM111A gene. Diagnosis of KCS2 can be challenging because of its similarities to other syndromes, the absence of clear hallmarks and the deficient number of genetically confirmed cases. Here, we aimed to further delineate and summarize the genotype and phenotype of KCS2, in order to get a better understanding of this rare disorder, and promote early diagnosis and intervention. METHODS: We present clinical and genetic characteristics of eight newly affected individuals with KCS2 from six families, including one family with three individuals found to be a father-to-daughter transmission, adding to the limited literature. Furthermore, we performed a review of genetically confirmed KCS2 cases in PubMed, MEDLINE and CNKI databases. RESULTS: There were six females and two males in our cohort. All the patients presented with short stature (100.0%). Clinical manifestations included ocular defects such as hypermetropia (5/8), dental problems such as defective dentition (3/8) and dental caries (3/8), skeletal and brain anomalies such as delayed closure of anterior fontanelle (6/8), cerebral calcification (3/8), cortical thickening (3/8) and medullary stenosis (4/8) of tubular bones. Endocrinologic abnormalities included hypoparathyroidism (5/8) and hypocalcemia (3/8). One male patient had micropenis and microorchidism. All cases harboured missense variants of FAM111A, and nucleotides c.1706 arose as a mutational hotspot, with seven individuals harbouring a c.1706G>A (p.Arg569His) variant, and one child harbouring a c.1531T>C (p.Tyr511His) variant. Literature review yielded a total of 46 patients from 20 papers. Data analysis showed that short stature, hypoparathyroidism and hypocalcemia, ocular and dental defects, skeletal features including cortical thickening and medullary stenosis of tubular bones, and seizures/spasms were present in more than 70% of the reported KCS2 cases. CONCLUSION: We provide detailed characteristics of the largest KCS2 group in China and present the first genetically confirmed instance of father-to-daughter transmission of KCS2. Our study confirms that Arg569His is the hot spot variant and summarizes the typical phenotypes of KCS2, which would help early diagnosis and intervention.


Asunto(s)
Caries Dental , Enanismo , Hiperostosis Cortical Congénita , Hipocalcemia , Hipoparatiroidismo , Niño , Femenino , Humanos , Masculino , Hipocalcemia/genética , Constricción Patológica , Fenotipo , Genotipo , Hipoparatiroidismo/genética
9.
Lipids Health Dis ; 23(1): 83, 2024 Mar 20.
Artículo en Inglés | MEDLINE | ID: mdl-38509578

RESUMEN

OBJECTIVE: To enhance the detection, management and monitoring of Chinese children afflicted with sitosterolemia by examining the physical characteristics and genetic makeup of pediatric patients. METHODS: In this group, 26 children were diagnosed with sitosterolemia, 24 of whom underwent genetic analysis. Patient family medical history, physical symptoms, tests for liver function, lipid levels, standard blood tests, phytosterol levels, cardiac/carotid artery ultrasounds, fundus examinations, and treatment were collected. RESULTS: The majority (19, 73.1%) of the 26 patients exhibited xanthomas as the most prevalent manifestation. The second most common symptoms were joint pain (7, 26.9%) and stunted growth (4, 15.4%). Among the 24 (92.3%) patients whose genetics were analyzed, 16 (66.7%) harbored ABCG5 variants (type 2 sitosterolemia), and nearly one-third (8, 33.3%) harbored ABCG8 variants (type 1 sitosterolemia). Additionally, the most common pathogenic ABCG5 variant was c.1166G > A (p.Arg389His), which was found in 10 patients (66.7%). Further analysis did not indicate any significant differences in pathological traits among those carrying ABCG5 and ABCG8 variations (P > 0.05). Interestingly, there was a greater abundance of nonsense variations in ABCG5 than in ABCG8 (P = 0.09), and a greater frequency of splicing variations in ABCG8 than ABCG5 (P = 0.01). Following a change in diet or a combination of ezetimibe, the levels of cholesterol and low-density lipoprotein were markedly decreased compared to the levels reported before treatment. CONCLUSION: Sitosterolemia should be considered for individuals presenting with xanthomas and increased cholesterol levels. Phytosterol testing and genetic analysis are important for early detection. Managing one's diet and taking ezetimibe can well control blood lipids.


Asunto(s)
Hipercolesterolemia , Enfermedades Intestinales , Errores Innatos del Metabolismo Lipídico , Fitosteroles , Fitosteroles/efectos adversos , Xantomatosis , Humanos , Niño , Lipoproteínas/genética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 5/genética , Fitosteroles/genética , Colesterol , Ezetimiba/uso terapéutico
10.
BMC Pediatr ; 24(1): 118, 2024 Feb 14.
Artículo en Inglés | MEDLINE | ID: mdl-38355440

RESUMEN

BACKGROUND: Prader-Willi syndrome (PWS) is a rare genetic disease often associated with bone problems, mainly scoliosis and hip dysplasia (HD). This study aimed to analyze the clinical characteristics of orthopedic deformities in patients with PWS. METHODS: A retrospective study was conducted on 175 patients up to March 2023. The Cobb angle(CA) of the spine, the alpha angle of the hip joint, and the acetabular index (AI) were measured. This study aimed to evaluate the relationship between demographic parameters and bone deformities. RESULTS: Scoliosis was found in 66 patients (43.7%), including 52 (78.8%) with mild scoliosis, 10 (15.2%) with moderate scoliosis, and 4 (6.1%) with severe scoliosis. Only seven patients received orthopedic treatment (10.6%). The median age of scoliosis was 4.5 years old, and the prevalence of scoliosis increased rapidly at the age of 5 years and adolescence. The mean CA in this study increased gradually with age. HD was found in 47 patients (38.2%), and 6 patients received orthopedic treatment (12.7%). The median age at HD was 1.8 years old. The mean AI of the study population decreased with age. The prevalence of HD treated with recombinant human growth hormone (rhGH) was low. No significant differences were observed in sex, genotype, body mass index (BMI), obesity rate, or onset of scoliosis and HD. CONCLUSION: The prevalence of scoliosis and HD was higher in patients with PWS. The onset age and developmental trends of the different skeletal malformations were different. Early diagnosis and treatment are important for the prognosis and treatment of orthopedic diseases in patients with PWS.


Asunto(s)
Hormona de Crecimiento Humana , Síndrome de Prader-Willi , Escoliosis , Niño , Adolescente , Humanos , Preescolar , Lactante , Síndrome de Prader-Willi/complicaciones , Síndrome de Prader-Willi/diagnóstico , Síndrome de Prader-Willi/tratamiento farmacológico , Escoliosis/etiología , Estudios Retrospectivos , Hormona de Crecimiento Humana/uso terapéutico , Obesidad/complicaciones
11.
Nat Commun ; 15(1): 987, 2024 Feb 02.
Artículo en Inglés | MEDLINE | ID: mdl-38307877

RESUMEN

Aberrant activation of sonic hedgehog (SHH) signaling and its effector transcriptional factor GLI1 are essential for oncogenesis of SHH-dependent medulloblastoma (MBSHH) and basal cell carcinoma (BCC). Here, we show that SHH inactivates p38α (MAPK14) in a smoothened-dependent manner, conversely, p38α directly phosphorylates GLI1 on Ser937/Ser941 (human/mouse) to induce GLI1's proteasomal degradation and negates the transcription of SHH signaling. As a result, Gli1S941E loss-of-function knock-in significantly reduces the incidence and severity of smoothened-M2 transgene-induced spontaneous MBSHH, whereas Gli1S941A gain-of-function knock-in phenocopies Gli1 transgene in causing BCC-like proliferation in skin. Correspondingly, phospho-Ser937-GLI1, a destabilized form of GLI1, positively correlates to the overall survival rate of children with MBSHH. Together, these findings indicate that SHH-induced p38α inactivation and subsequent GLI1 dephosphorylation and stabilization in controlling SHH signaling and may provide avenues for future interventions of MBSHH and BCC.


Asunto(s)
Neoplasias Cerebelosas , Meduloblastoma , Animales , Niño , Humanos , Ratones , Neoplasias Cerebelosas/genética , Proteínas Hedgehog/metabolismo , Meduloblastoma/genética , Meduloblastoma/patología , Oncogenes , Fosforilación , Proteína con Dedos de Zinc GLI1/genética , Proteína con Dedos de Zinc GLI1/metabolismo
13.
Clin Genet ; 105(4): 415-422, 2024 04.
Artículo en Inglés | MEDLINE | ID: mdl-38258470

RESUMEN

The genotype-phenotype relationship in PWS patients is important for a better understanding of the clinical phenotype and clinical characteristics of different genotypes of PWS in children. We aimed to explore the influence of specific gene changes on the clinical symptoms of PWS and the value of early screening and early intervention of the condition. All data in this study were extracted from the database of the XiaoPang Weili Rare Disease Care Center. The collected information included basic demographics, maternal pregnancy information, endocrine abnormalities, growth and development abnormalities, and other clinical phenotypes. The relationships between genotypes and phenotypes in the major categories of PWS were analyzed. A total of 586 PWS cases with confirmed molecular diagnosis and genotyping were included in this study. Among them, 83.8% belonged to the deletion type, 10.9% the uniparental disomy (UPD) type, and 5.3% the imprinting defect (ID) type. Age-wide comparison among the three groups: The rate of hypopigmentation in the deletion group was higher than that in the UPD group (88.8% vs. 60.9%; p < 0.05); A total of 62 patients (14.2%) had epilepsy; and no statistical significance was found among the three groups (p = 0.110). Age-wide comparison between the deletion and non-deletion types: the rate of skin hypopigmentation and epilepsy in the deletion group was significantly higher than that in the non-deletion group (88.8% vs. 68.4%, p < 0.001; 15.9% vs. 7.6%, p = 0.040). The intergroup comparison for the >2-year age group: there were significant intergroup differences in the language development delay among the three groups (p < 0.001). The incidence of delayed language development was the highest in the deletion group, followed by the UPD group, and the lowest in the ID group. The rates of obesity and hyperphagia in the deletion group were also higher than those in the non-deletion group (71.1% vs. 58.9%, p = 0.041; 75.7% vs. 62.0%, p = 0.016). There are significant differences in the rates of skin hypopigmentation and language developmental delay among the deletion, UPD, and ID genotypes. The patients with deletion type had significantly higher rates of lighter skin color, obesity, hyperphagia, language developmental delay, and epilepsy. The results of this study will help clinicians better understand the impact of different PWS molecular etiologies on specific phenotypes.


Asunto(s)
Epilepsia , Hipopigmentación , Síndrome de Prader-Willi , Niño , Embarazo , Femenino , Humanos , Síndrome de Prader-Willi/epidemiología , Síndrome de Prader-Willi/genética , Síndrome de Prader-Willi/diagnóstico , Disomía Uniparental/genética , Fenotipo , Hiperfagia/complicaciones , Estudios de Asociación Genética , China/epidemiología , Epilepsia/complicaciones , Cromosomas Humanos Par 15
15.
Front Pediatr ; 11: 1198906, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37441566

RESUMEN

The NAA10 gene encodes the catalytic subunit of the N-terminal acetyltransferase protein complex A (NatA), which is supposed to acetylate approximately 40% of the human proteins. After the advent of next-generation sequencing, more variants in the NAA10 gene and Ogden syndrome (OMIM# 300855) have been reported. Individuals with NAA10-related syndrome have a wide spectrum of clinical manifestations and the genotype-phenotype correlation is still far from being confirmed. Here, we report a three years old Chinese girl carrying a heterozygous de novo NAA10 [NM_003491: c. 247C > T, p. (Arg83Cys)] variant (dbSNP# rs387906701) (ClinVar# 208664) (OMIM# 300013.0010). The proband not only has some mild and common clinical manifestations, including dysmorphic features, developmental delay, obstructive hypertrophic cardiomyopathy, and arrhythmia, but also shows some rare clinical features such as exophthalmos, blue sclera, cutaneous capillary malformations, and adenoid hypertrophy. Our attempt is to expand the clinical phenotype associated with NAA10-related syndrome and explore genotype-phenotype correlation with such syndrome.

16.
RNA Biol ; 20(1): 419-430, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-37405372

RESUMEN

The genetic disorder Prader-Willi syndrome (PWS) is mainly caused by the loss of multiple paternally expressed genes in chromosome 15q11-q13 (the PWS region). Early diagnosis of PWS is essential for timely treatment, leading to effectively easing some clinical symptoms. Molecular approaches for PWS diagnosis at the DNA level are available, but the diagnosis of PWS at the RNA level has been limited. Here, we show that a cluster of paternally transcribed snoRNA-ended long noncoding RNAs (sno-lncRNAs, sno-lncRNA1-5) derived from the SNORD116 locus in the PWS region can serve as diagnostic markers. In particular, quantification analysis has revealed that 6,000 copies of sno-lncRNA3 are present in 1 µL whole blood samples from non-PWS individuals. sno-lncRNA3 is absent in all examined whole blood samples of 8 PWS individuals compared to 42 non-PWS individuals and dried blood samples of 35 PWS individuals compared to 24 non-PWS individuals. Further developing a new CRISPR-MhdCas13c system for RNA detection with a sensitivity of 10 molecules per µL has ensured sno-lncRNA3 detection in non-PWS, but not PWS individuals. Together, we suggest that the absence of sno-lncRNA3 represents a potential marker for PWS diagnosis that can be detected by both RT-qPCR and CRISPR-MhdCas13c systems with only microlitre amount of blood samples. Such an RNA-based sensitive and convenient approach may facilitate the early detection of PWS.


Asunto(s)
Síndrome de Prader-Willi , ARN Largo no Codificante , Humanos , Síndrome de Prader-Willi/diagnóstico , Síndrome de Prader-Willi/genética , ARN Largo no Codificante/genética , ARN Nucleolar Pequeño/genética
17.
Front Public Health ; 11: 1177317, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37361163

RESUMEN

Introduction: Williams syndrome (WS) is a rare genetic disorder that impacts multiple systems and may cause developmental delays. These medical and developmental issues impose a heavy burden on affected children and their families. However, there was no study on children's health-related quality of life (HRQoL) with WS and only two studies about family quality of life globally. Therefore, the primary purpose of this study was to assess the HRQoL of children with WS and their caregivers in China, and the secondary purpose was to identify the potential determinants of children's and caregivers' HRQoL. Methods: In total, 101 children and caregivers were included. We applied the proxy-reported PedsQL 4.0 Generic Core Module (PedsQL GCM) and PedsQL 3.0 Family Impact Module (FIM) to measure the HRQoL of children and caregivers. Additionally, we collected information on a comprehensive set of social demographic and clinical characteristics. Differences in HRQoL scores across subgroups were assessed by two-independent-samples t-tests, one-way ANOVA, and post hoc tests. We also calculated effect sizes to indicate clinical relevance. Multivariate linear regression models were applied to assess the potential determinants of HRQoL. Results: We found that the HRQoL of children with WS and their caregivers was dramatically worse than the norm average scores of the healthy controls of children published in previous studies. Paternal educational level, household income, and the perceived financial burden significantly influenced the HRQoL of both children and families (p-values < 0.05). Multivariate linear regression analysis showed that the perceived financial burden was independently associated with family quality of life (p-values < 0.05)., and the presence of sleeping problem was independently associated with children's HRQoL (p-value = 0.01). Conclusion: We call for attention from policymakers and other stakeholders on the health status and well-being of children with WS and their families. Supports are needed to relieve psychosocial distress and financial burden.


Asunto(s)
Calidad de Vida , Síndrome de Williams , Humanos , Niño , Calidad de Vida/psicología , Cuidadores/psicología , Estado de Salud , China
18.
Artículo en Inglés | MEDLINE | ID: mdl-37074093

RESUMEN

Thyroid storm is a rare but life-threatening condition mainly triggered by infection and abrupt discontinuation of antithyroid drug therapy for Graves' disease. Pancytopenia is a rare adverse reaction to antithyroid drugs. We present a 13-year-old girl with thyroid storm and pancytopenia with symptoms similar to those of methimazole-induced pancytopenia. Although in this context the use of methimazole is still under debate, due to multiple normal complete blood counts monitored during fever, sepsis-induced pancytopenia with thyroid storm was considered, and methimazole treatment combined with methylprednisolone and meropenem was able to resolve both pancytopenia and thyroid storm. During the period of infection and antithyroid drug therapy, close monitoring of complete blood count may help differentiate the aetiology of pancytopenia. This is the first paediatric case report that outlines the use of methimazole in the management of thyroid storm with pancytopenia.

19.
Orphanet J Rare Dis ; 18(1): 25, 2023 02 07.
Artículo en Inglés | MEDLINE | ID: mdl-36750945

RESUMEN

BACKGROUND: Prader-Willi syndrome (PWS) is a rare and multisystemic genetic disorder that is characterized by severe hypotonia, hyperphagia, short stature, and global developmental delay. Although early recombinant human growth hormone (rhGH) treatment has been proven to rescue some symptoms and bring additional benefits to PWS patients, studies in patients under 2 years old are scarce. Thus, this study aims to investigate the effectiveness and safety of rhGH treatment for young children. METHODS: A total of 96 genetically confirmed Chinese PWS infants or toddlers (47 males) followed between 2013 and 2022 were retrospectively analyzed. Sixty-five infants (early treatment group) started rhGH treatment during their first year, and 31 toddlers (later treatment group) started at the age of 1-2 years. Auxological parameters, carbohydrate metabolism parameters, thyroid function, liver function, insulin-like growth factor-1 (IGF-1), and radiographs were acquired before the initiation of the treatment and every 3-6 months thereafter. Height/length, weight, and weight for height were expressed as standard deviation scores (SDSs) according to WHO child growth standards. RESULTS: The mean SDS of length/height in the early treatment group was significantly higher than that in the later treatment group throughout the observation period (all P < 0.001). The change in the length SDS between the two groups at 1 year old and 4 years old was 1.50 (95% CI, 0.88-2.13) and 0.63 (95% CI, 0.16-1.10), respectively. Compared to the later treatment group, the weight SDS in the early treatment group increased by 0.94 (95% CI, 0.37-1.52) at 1 year old and 0.84 (95% CI, 0.28-1.39) at 2 years old. No statistical significance was found after 2.5 years of age. No significant differences were observed in IGF-1, incidence of liver dysfunction, hypothyroidism or spinal deformity between the two groups. CONCLUSIONS: rhGH treatment improved growth and body composition in infants and toddlers. Furthermore, an early start of rhGH treatment is expected to have more efficacy than the later treatment group without an increase in adverse effects.


Asunto(s)
Hormona de Crecimiento Humana , Síndrome de Prader-Willi , Preescolar , Humanos , Lactante , Masculino , Pueblos del Este de Asia , Hormona de Crecimiento Humana/uso terapéutico , Factor I del Crecimiento Similar a la Insulina/metabolismo , Síndrome de Prader-Willi/tratamiento farmacológico , Proteínas Recombinantes/uso terapéutico , Estudios Retrospectivos , Femenino
20.
Front Pediatr ; 10: 1027832, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36467480

RESUMEN

The myelin regulatory factor (MYRF; MIM# 608329) gene was first identified as a critical transcription factor involved in oligodendrocyte differentiation and central nervous system myelination. With the recent development of exome sequencing, pathogenic variants of MYRF had been considered as the cause of cardiac-urogenital syndrome (CUGS), 46,XY and 46,XX disorders/differences of sex development (DSDs), and nanophthalmos. Herein, we described a 4-year-7-month-old "girl" with ventricular septal defect, atrial septal defect, patent ductus arteriosus, severe pulmonary hypertension, moderate-to-severe tricuspid regurgitation, enlarged coronary sinus, left superior vena cava, and right lung hypoplasia at birth. Later, the patient developed short stature and amblyopia. Further examination revealed a karyotype 46,XY and visible uterus, whereas the presence of gonads were not explored. Laparoscopy revealed dysplasia of testicular gonad. Whole-exome sequencing (WES) was performed and a de novo heterozygous mutation in MYRF was identified, known as c.2817G > A/p. W939* (NM_001127392.3). Therefore, this case report presented multiple clinical manifestations with syndromic symptoms of CUGS, 46,XY DSD, and ocular symptoms. These new data expanded the phenotype of the MYRF variant and may benefit to characterize the phenotypes caused by the variants of this gene.

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